Directly Reprogrammed Human Neurons Retain Aging-Associated Transcriptomic Signatures and Reveal Age-Related Nucleocytoplasmic Defects

Jerome Mertens, Apuã C.M. Paquola, Manching Ku, Emily Hatch, Lena Böhnke, Shauheen Ladjevardi, Sean McGrath, Benjamin Campbell, Hyungjun Lee, Joseph R. Herdy, J. Tiago Gonçalves, Tomohisa Toda, Yongsung Kim, Jürgen Winkler, Jun Yao, Martin W. Hetzer, Fred H. Gage

Research output: Contribution to journalArticle

Abstract

Aging is a major risk factor for many human diseases, and in vitro generation of human neurons is an attractive approach for modeling aging-related brain disorders. However, modeling aging in differentiated human neurons has proved challenging. We generated neurons from human donors across a broad range of ages, either by iPSC-based reprogramming and differentiation or by direct conversion into induced neurons (iNs). While iPSCs and derived neurons did not retain aging-associated gene signatures, iNs displayed age-specific transcriptional profiles and revealed age-associated decreases in the nuclear transport receptor RanBP17. We detected an age-dependent loss of nucleocytoplasmic compartmentalization (NCC) in donor fibroblasts and corresponding iNs and found that reduced RanBP17 impaired NCC in young cells, while iPSC rejuvenation restored NCC in aged cells. These results show that iNs retain important aging-related signatures, thus allowing modeling of the aging process in vitro, and they identify impaired NCC as an important factor in human aging.

Original languageEnglish (US)
Pages (from-to)705-718
Number of pages14
JournalCell stem cell
Volume17
Issue number6
DOIs
StatePublished - Dec 3 2015

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ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

Cite this

Mertens, J., Paquola, A. C. M., Ku, M., Hatch, E., Böhnke, L., Ladjevardi, S., McGrath, S., Campbell, B., Lee, H., Herdy, J. R., Gonçalves, J. T., Toda, T., Kim, Y., Winkler, J., Yao, J., Hetzer, M. W., & Gage, F. H. (2015). Directly Reprogrammed Human Neurons Retain Aging-Associated Transcriptomic Signatures and Reveal Age-Related Nucleocytoplasmic Defects. Cell stem cell, 17(6), 705-718. https://doi.org/10.1016/j.stem.2015.09.001